This mentored clinician-scientist award (K08) proposal is a five-year plan to enable the candidate to develop into an independent investigator in the genetics of bipolar disorder. As a fully trained psychiatrist with sub-specialty experience in affective disorder, the candidate has an excellent grasp of the phenotype. This proposal provides for extensive development of his skills in molecular genetic methods. There will also be opportunities to learn statistical genetic methods. This will be accomplished through formal course work, extensive mentorship in a collaborative research environment, and implementation of a study that will be the first step toward a larger body of research aimed at investigating the genetics of bipolar disorder. Mentorship will be provided by Dr. J. Raymond DePaulo, Jr., the director of the affective disorders genetics research group at Johns Hopkins, and by Dr. Andrew Feinberg, an expert on genomic imprinting at the Johns Hopkins Center for Medical Genetics. Dr. Terri Beaty, director of genetic epidemiology at the Johns Hopkins School of Public Health will provide valuable consultation in statistical genetics methods. The training program will be enhanced by a research plan based on the hypothesis that the parent-of-origin-specific expression of imprinted genes modifies susceptibility to bipolar disorder. This hypothesis derives from clinical evidence for a parent-of-origin effect in transmission of the disorder, from linkage evidence for a parent-of-origin effect on chromosome 18, and from linkage evidence for a parent-of-origin effect in other areas of the genome. The candidate intends to take advantage of two valuable existing bipolar disorder family data sets collected under the direction of Dr. DePaulo as well as a third currently being ascertained. The specific aims are as follows: 1) to identify transcribed single nucleotide polymorphisms in genes from a candidate region for bipolar disorder on chromosome 1 8q; 2) to search for imprinted bipolar disorder susceptibility genes on chromosome 18 by testing for monoallelic expression of mRNA; and 3) to perform parental-allele-specific genetic analysis of other chromosomal regions.